Chalcone is a class of flavonoid compounds that are widely biosynthesized in plants. Epidemiological studies suggest that increased intake of flavonoids from fruits and vegetables reduces the risk of cardiovascular disease. However, the effect of chalcone on cardiovascular diseases has not been fully investigated. The aims of this study were to evaluate the antiatherosclerotic effect of 2-hydroxy-4'-methoxychalcone (AN07, a synthetic chalcone derivate) and to investigate its potential pharmacological mechanisms. Oxidized low-density lipoprotein (Ox-LDL) has been reported to stimulate proliferation of human aortic smooth muscle cells and that is one of the mechanisms resulting in atherosclerosis. In this study, we demonstrate that AN07 significantly inhibits the Ox-LDL-induced proliferation of human aortic smooth muscle cells. This effect is mediated via the inhibition of p44/42 mitogen-activated protein kinase and E-twenty six 1 phosphorylations. In the effect of anti-inflammation, AN07 decreases the Ox-LDL-stimulated upregulation of interleukin (IL) 1β and IL-6. In addition, AN07 acts synergistically with rosiglitazone and pioglitazone to inhibit the Ox-LDL-induced proliferation of human aortic smooth muscle cells and upregulation of cyclin D1, cyclin D3, IL-1β, and IL-6. These effects are a result of an increase in peroxisome proliferator-activated receptor gamma mRNA and protein expression stimulated by AN07 in human aortic smooth muscle cells. In conclusion, the chalcone derivate AN07 has versatile therapeutic potential against atherosclerosis by acting as peroxisome proliferator-activated receptor gamma inducer, p44/42 mitogen-activated protein kinase inhibitor, and cell cycle blocker.